Mutant Kras is a druggable target for pancreatic cancer

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge.
PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target.
We propose an approach to target KRAS effectively in patients using RNA interference.
To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (KRAS-LODER).
The KRAS-LODER was assessed for its structural, release, and delivery properties in vitro and in vivo.
The effect of the KRAS-LODER on tumor growth was assessed in s.c. and orthotopic mouse models.
KRAS silencing effect was further assessed on the KRAS downstream signaling pathway.
The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with KRAS-LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial–mesenchymal transition.
In vivo, KRAS-LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival.
We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA.
This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the KRAS-LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.

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Ilan Hadar- Chairman

55, has served as Managing Director of Silexion since April 2022 and as Chairman of the Board since May 2024. Ilan has been appointed as Chief Executive Officer of New Pubco. He has over 20 years of multinational managerial and corporate experience with pharmaceutical and high-tech companies, as described below, over which time period he has acquired the experience and skills to serve as a valuable member of the board of directors of a company such as Biomotion Sciences. before his current role at Silexion, Mr. Hadar has served as the Chief Executive Officer of Painreform Ltd (Nasdaq: PRFX) since November 2020. Before joining Painreform, Mr. Hadar served as Country Manager in Israel and Chief Financial Officer at Foamix Pharmaceuticals Ltd. (currently, Nasdaq: VYNE) from 2014 until August 2020, where he was instrumental in building the organization and launching new innovative topical drugs in the U.S., and also focused on capital markets and mergers and acquisitions. Prior to his role at Foamix, Mr. Hadar was Finance Director at Pfizer PFR Pharmaceuticals Israel Ltd., where he oversaw all commercial, financial and operational activities of the local entity of the large pharmaceutical company. Before his tenure at Pfizer, Mr. Hadar served as Finance Manager at HP Indigo Ltd., a world-leading company in digital printing and, prior to that, served as Finance Director at BAE Systems, the third-largest defense company in the world, where he was responsible for all financial activities of BAE Systems Israel. From 1998 to 2006, Mr. Hadar was the Chief Financial Officer at Mango DSP, a global leader in Intelligent Video Solutions. Mr. Hadar served on the board of directors of Kadimastem, a public Israeli biopharmaceutical company from 2019 to 2022. He received his MBA in Finance and Business Entrepreneurship and BA from The Hebrew University in Jerusalem, Israel.

Mirit Horenshtein Hadar- Chief Finanacial Officer

Has served as the Executive Vice President of Finance Affairs at Silexion since January 2024, and will be appointed as Chief Financial Officer of New Pubco effective upon the consummation of the Business Combination. From August 2023 to January 2024, Ms. Horenshtein Hadar served as a part-time consultant in a Strategy & Corporate Finance Advisory capacity. Ms. Horenshtein Hadar has over 15 years ofcorporate finance experience in senior financial positions of public companies and privately held companies, in the pharmaceutical and high-tech industries, where she has been instrumental in building financial infrastructures for growth, U.S. GAAP financial reporting and FP&A functions, and has led the accounting and reporting of complex M&A transactions, integration processes and public offerings. Prior to joining Silexion, from January 2021 to December 2022, Ms. Horenshtein Hadar served as VP of Finance and then CFO Israel of Gauzy Ltd. (currently, Nasdaq: GAUZ), a nanotechnology company that develops and markets smart glass and vision control technologies. Since December 2022, Ms. Horenshtein Hadar continues to serve as an external advisor to the finance department at Gauzy. Prior to Gauzy, Ms. Horenshtein Hadar served as Senior Director of Finance and Head of FP&A, Accounting and Financial Reporting at Foamix Pharmaceuticals Ltd. (currently, Nasdaq: VYNE) from July 2016 until December 2020. Prior to Foamix, Ms. Horenshtein Hadar was a Senior Manager at PwC Israel, as an external auditor, from 2008 to 2016. Ms. Horenshtein Hadar became a Qualified CPA in 2011 and received a BA in Accounting, Economics and Business Management from Tel Aviv University.

Orit Pollack–Shragai, M.Sc, MBA- VP Clinical Operations

Mrs. Pollack Shragai brings  over  two  decades  of relevant academic education, research and work experience in the biomed industry working for CRO, big pharma and start-up companies, managing local and international clinical trials (including mega trials) in drugs and medical devices. Prior to joining Silenseed, Mrs. Pollack Shragai served as Director of Clinical Operations and Active Advisor to several pharmaceutical companies 

Mrs. Pollack Shragai holds a  B.Sc  in  Food  Engineering  and  Biotechnology  from  the  Technion  in  Israel,  M.Sc  in Biotechnology  from  the  Hebrew  University  and  MBA  from  the  College  of  Management Academic Studies.

Michal Yaron- VP Regulatory Affairs

Mrs. Yaron holds 17 years of professional regulatory and product development experience across the pharmaceutical industry, with products from early stage through POC and regulatory approvals by multiple health authorities. Previously Mrs. Yaron held Regulatory Affairs managerial positions at Sol-Gel Technologies, Polypid, and Teva Pharmaceuticals Ltd. Mrs. Yaron Holds a M.Sc. degree in Chemistry.

Dr. Revital Maor Aloni

Dr. Revital Maor Aloni Joined Silenseed in December 2019 and led the quality of the KRAS-LODER from phase II. She also led the process for gaining a GMP approval from the Israeli Ministry of health for the LODER. Prior to joining Silenseed Dr. Maor Aloni has served as Director of Quality in SciVak Ltd. a biotechnology company from 2017, and prior to that as Director of Quality systems in Lumenis, a medical device company. Dr. Maor Aloni also served as senior manager in Aminolab Ltd. For 6 years as head of the Microbiology department and the chemistry department. Dr. Maor Aloni holds a Ph. D in microbiology from Ben-Gurion University in Beer-Sheva and Post-Doctorate from the Weizmann Institute of Science in Rehovot, Israel.

Dr. Racheli Malka Gabai

VP Pharmaceutical Development, Ph. D- Dr Gabai Malka Joined Silenseed in February 2009 and leads the development of the formulation and the production of the KRAS-LODER from the concept stage and up to Phase II. Dr Gabai Malka holds a B.Sc. in Chemistry and a M.Sc. in Chemistry both from the Hebrew University in Jerusalem and holds a Ph.D. and a Post-Doctorate in Chemistry from the Weizmann institute of science in Rehovot, Israel.

Dr Gabai Malka is a co-author of 12 scientific papers and co-inventor of 8 of the Silenseed’s granted patents.

Dr. Mitchell Shirvan - Chief Scientific and Development Officer

Has served as the Chief Scientific and Development Officer of Silexion since April 2022. Prior to joining Silexion, Dr. Shirvan served as the Senior Vice President of R&D and V.P. Innovation and Discovery at Foamix Pharmaceuticals Ltd. from 2014 to 2019. Dr. Shirvan has over 25 years of industry experience, previously holding positions as Chief Executive Officer at Macrocure Ltd. from 2008 to 2012. From 1992 until 2008, Dr. Shirvan held various positions of increasing responsibility at Teva Pharmaceutical Industries, including Senior Director, Strategic Business Planning and Senior Manager, Research & Development. Prior to his tenure at Teva, he was a research fellow at the U.S. National Institutes of Health. Dr. Shirvan holds a Ph.D. in microbiology from The Hebrew University of Jerusalem and an MBA from the University of Bradford.

Ilan Hadar – Chief Executive Officer

Mr. Hadar brings over 20 years of multinational managerial and corporate experience with pharmaceutical and high-tech companies. Ilan has been instrumental in building companies from start-ups to hundreds of millions of dollars in operations. He successfully took part in the development, approval, and launch of new pharmaceutical products in the U.S. and Israel. Before joining Seilexion, Ilan is served as the Chief Executive Officer of Painreform Ltd. (“PRFX”) from Nov. 2020 to June 2024. Painreform proprietary extended-release drug-delivery system is designed to provide an extended period of post-surgical pain relief without the need for repeated dose administration. Prior to joining Painreform, Ilan served as Country Manager Israel and Chief Financial Officer at Foamix Pharmaceuticals Ltd. (now NASDAQ: VYNE) since 2014, where he was instrumental in building the organization and launching new innovative topical drugs in the U.S., as well as a focus on capital markets and M&A. Prior to Foamix, Ilan was Finance Director at Pfizer Pharmaceutical Ltd., where he oversaw all commercial, financial and operational activities of the local entity. Ilan served on the Board of Directors at Kadimastem, a public Israeli biopharmaceutical company (TASE: KDST). Ilan received his MBA in Finance and Business Entrepreneurship and B.A. degree at The Hebrew University in Jerusalem, Israel.